Dataset Information

Antibody microarray analysis of serum inflammatory cytokines in patients with calcific aortic valve disease.

ABSTRACT:

Background

Calcific aortic valve disease (CAVD) is a slowly progressive pathologic process associated with significant morbidity and mortality, CAVD is the most common valve heart disease in the elderly and a leading cause of aortic valve stenosis. Multiple steps characterize the process: inflammation, cell apoptosis, lipid deposition, renin-angiotensin system activation, extracellular matrix remodeling, and bone formation. This paper focuses on detecting and analyzing the expression of serum inflammatory factors in CAVD by antibody microarray techniques.

Methods

In this study, a total of 258 patients were included at Tianjin Chest Hospital between January 2017 and December 2018, subjects were divided into three groups: control, coronary artery disease (CAD), and CAVD. Blood samples were collected, and adipokine/cytokine/chemokine serum profiles were measured by antibody arrays.

Results

These data suggest that B-Lymphocyte Chemoattractant (BLC), Interleukin (IL)-12p40, monokine inducible by γ interferon (MIG), and Macrophage inflammatory protein (MIP)-1delta were significantly increased in CAVD compared to control or CAD. Furthermore, Real-time quantified PCR, Western blot assay, and Flow cytometer detection showed that these four cytokines/chemokines were from peripheral blood mononuclear cells.

Conclusions

These findings suggest that BLC, IL-12p40, MIG, and MIP-1delta can be used as a marker to assess CAVD, which could have significant clinical implications.

SUBMITTER: Fu B

PROVIDER: S-EPMC7333163 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Antibody microarray analysis of serum inflammatory cytokines in patients with calcific aortic valve disease.

Fu Bo B Zhang Yuhui Y Chen Qingliang Q Guo Zhigang Z Jiang Nan N

Annals of translational medicine 20200601 12

<h4>Background</h4>Calcific aortic valve disease (CAVD) is a slowly progressive pathologic process associated with significant morbidity and mortality, CAVD is the most common valve heart disease in the elderly and a leading cause of aortic valve stenosis. Multiple steps characterize the process: inflammation, cell apoptosis, lipid deposition, renin-angiotensin system activation, extracellular matrix remodeling, and bone formation. This paper focuses on detecting and analyzing the expression of ...[more]

PMID: 32647686

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Project description:Calcific Aortic Valve Disease (CAVD) is the most frequent valvular heart disease in developed countries. It is characterized by a progressive calcification of aortic valve leaflets mediated by myeloid cells, such as monocytes and macrophages. However, the molecular mechanisms involved in their recruitment and activity are still poorly understood and limit the development of a pharmacological treatments. Previous studies have already demonstrated the role of macrophages in CAVD development. However, little is known about the implication of their precursors, monocytes. Thus, we hypothesized that circulating monocytes from CAVD patients have higher pro-calcific and pro-inflammatory capacities. We aimed first to assess the pro-calcifying potential of circulating monocytes from patients with CAVD and second to better understand the molecular mechanisms of this pro-calcific effect through a whole transcriptomic study. Methods : We first characterized monocytes sub-population, from PBMCs isolated from peripheral blood of healthy volunteers (Vol) and patients with CAVD or without CAVD (NCAVD), with flow cytometry. Then we analyzed the whole transcriptome of these monocytes by RNA sequencing (RNAseq) to identify dysregulated genes expression, further confirmed by RT-qPCR. Finally, after evaluation of monocytes secretome with multiplex analysis, we evaluated CAVD monocytes capacities to induce myofibroblastic transdifferenciation and osteoblastic differencitation of human valvular interstitial cells (hVIC) with immunocytochemistry (ICC) and O-cresolphtalein assay. Results : In CAVD (calcific aortic valve disease) monocytes, we observe a shift in their sub-populations, with an increased frequency of classical monocytes (CD14+CD16-) and a decreased frequency of non-classical monocytes (CD14+CD16++). Interestingly, we found specific upregulation of genes linked to both inflammation (PDK4) and calcification (ATP2B1), alongside the downregulation of immunomodulatory genes (DDR1, IKBKE) in monocytes from CAVD patients. Additionally, CAVD monocytes produce lower levels of immunomodulatory and anti-osteoblastogenic cytokines (IL3, CCL3), which promote myofibroblastic transdifferentiation (TIMP1, TNC) and osteoblastic differentiation (ALPL, OPG). This correlates with an increase in αsma+ and opn+ cells and a doubling of hVIC calcifications. Conclusions : We demonstrated for the first time that circulating monocytes from CAVD patients have higher pro-inflammatory and pro-calcific capacities that might promote CAVD development. Likewise, we identify dysregulated genes, which could be used as new therapeutic targets.

Project description:Calcific aortic valve disease (CAVD) is characterized by progressive stiffening of aortic valve (AV) tissues, inducing stenosis and insufficiency. Bicuspid aortic valve (BAV) is a common congenital defect in which the AV has two leaflets rather than three, with BAV patients developing CAVD decades years earlier than in the general population. Current treatment for CAVD remains surgical replacement with its continued durability problems, as there are no pharmaceutical therapies or other alternative treatments available. Before such therapeutic approaches can be developed, a deeper understanding of CAVD disease mechanisms is clearly required. It is known that AV interstitial cells (AVICs) maintain the AV extracellular matrix and are typically quiescent in the normal state, transitioning into an activated, myofibroblast-like state during periods of growth or disease. One proposed mechanism of CAVD is the subsequent transition of AVICs into an osteoblast-like phenotype. A sensitive indicator of AVIC phenotypic state is enhanced basal contractility (tonus), so that AVICs from diseased AV will exhibit a higher basal tonus level. The goals of the present study were thus to assess the hypothesis that different human CAVD states lead to different biophysical AVIC states. To accomplish this, we characterized AVIC basal tonus behaviors from diseased human AV tissues embedded in 3D hydrogels. Established methods were utilized to track AVIC-induced gel displacements and shape changes after the application of Cytochalasin D (an actin polymerization inhibitor) to depolymerize the AVIC stress fibers. Results indicated that human diseased AVICs from the non-calcified region of TAVs were significantly more activated than AVICs from the corresponding calcified region. In addition, AVICs from the raphe region of BAVs were more activated than from the non-raphe region. Interestingly, we observed significantly greater basal tonus levels in females compared to males. Furthermore, the overall AVIC shape changes after Cytochalasin suggested that AVICs from TAVs and BAVs develop different stress fiber architectures. These findings are the first evidence of sex-specific differences in basal tonus state in human AVICs in varying disease states. Future studies are underway to quantify stress fiber mechanical behaviors to further elucidate CAVD disease mechanisms.

Dataset Information

Antibody microarray analysis of serum inflammatory cytokines in patients with calcific aortic valve disease.

Background

Methods

Results

Conclusions

Publications

Antibody microarray analysis of serum inflammatory cytokines in patients with calcific aortic valve disease.

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